7. Project Summary/Abstract Due to cervical spinal cord injury, many patients are dependent upon lifelong mechanical ventilatory support. While electrical stimulation techniques have been useful in liberating some patients from mechanical ventilation, the vast majority is still dependent on these devices. Due to their significant disadvantages, additional pacing options are badly needed. We have demonstrated in an animal model of spinal cord injury that inspiratory muscle activation can be achieved with upper thoracic high frequency (~300 Hz) spinal cord stimulation (HF-SCS) with low stimulus amplitudes. This unique and exciting innovative method involves stimulation of spinal cord circuitry, resulting in a more physiologic pattern of inspiratory muscle activation. However, critically important aspects of this method require characterization and analysis prior to clinical application, particularly in view of the fact that this method represents a life support system. In Objective 1, we plan to evaluate the possible involvement of long descending inspiratory bulbospinal fibers on the efficacy of HF-SCS, in a sub-acute animal model of spinal cord injury. Since the spinal cord undergoes significant plasticity beyond this period, we will also evaluate the efficacy of HF-SCS in a chronic cervical hemi-sected rat model over a period of 8 weeks. In Objective 2, we will examine the mechanism of HF-SCS with the development of a validated computational model, which will be used to predict optimal stimulus paradigms and optimal electrode designs; these will subsequently tested in our animal model. In Objective 3, various stimulus paradigms derived from computational model predictions will be validated. An optimal pattern of stimulation should result in the physiologic participation of each of the inspiratory muscle groups, normal gas exchange and have low electrical charge requirements. In Objective 4, we will determine the degree to which HF-SCS results in physiologic activation of the inspiratory muscles by assessing motor unit recruitment order. In Objective 5, we will assess the degree to which opposing expiratory muscles are activated during HF-SCS. In addition, a more detailed analysis of potential non-inspiratory muscle activation will be determined by evaluating the metabolic cost of breathing during HF-SCS. In summary, the results of these studies should resolve the important basic science and practical issues concerning HF-SCS in advance of clinical trials. If successful, HF-SCS may provide a more natural and effective method of inspiratory muscle activation and is likely to reduce the number of tetraplegics dependent upon mechanical ventilation and thereby significantly improve their life quality.